Figure 3. Opportunities for future molecularly targeted therapy for glioblastoma.

(A) The primary tumor is heterogeneous, and composed of several abundant cell subpopulations: cells with variable proliferation properties (pink and green), glioma stem cells (GSCs) (tan), and recurrence-initiating stem-like cancer (RISC) cells (red). Initial treatments successfully reduce the bulk tumor volume and its heterogeneity. However, subpopulations of RISC cells survive therapeutic intervention though intrinsic and adaptive resistance mechanisms (indicated by a blue ring). RISC cells initiate tumor recurrence through a second round of clonal evolution that repopulates the tumor. The current clinical strategies for GBM could be strengthened by adding molecular therapies to target: (i) initially resistant clones, (ii) adaptive resistance mechanisms, and (iii) the tumor when its population diversity and cell numbers are at their lowest. (B) Schematic showing the 4 proposed different cancer cell populations in the tumor (GSCs [tan], RISC cells [red], non-GSCs [light blue], and proliferating non-GSCs [dark blue]) and putative ways to target them (see also Table 2). RISC cells likely represent a subset of the GSC population with both innate and acquired resistance. The precise proportion of each cell population remains to be established. (C) Proposed optimal timing for each therapeutic option during the initial (primary treatment) and intermediate (stabilization/remission period before recurrence) phases of therapy.